Australian National Standards of Care for Childhood-onset Heart Disease (CoHD Standards). 1st Edition.

These first Australian National Standards of Care for Childhood-onset Heart Disease (CoHD Standards) have been developed to inform the healthcare requirements for CoHD services and enable all Australian patients, families and carers impacted by CoHD (paediatric CoHD and adult congenital heart disease [ACHD]) to live their best and healthiest lives. The CoHD Standards are designed to provide the clarity and certainty required for healthcare services to deliver excellent, comprehensive, inclusive, and equitable CoHD care across Australia for patients, families and carers, and offer an iterative roadmap to the future of these services. The CoHD Standards provide a framework for excellent CoHD care, encompassing key requirements and expectations for whole-of-life, holistic and connected healthcare service delivery. The CoHD Standards should be implemented in health services in conjunction with the National Safety and Quality Health Service Standards developed by the Australian Commission on Safety and Quality in Health Care. All healthcare services should comply with the CoHD Standards, as well as working to their organisation's or jurisdiction's agreed clinical governance framework, to guide the implementation of structures and processes that support safe care.

Thrombopoietin receptor agonist discontinuation rates and reasons among patients with immune thrombocytopenia: a study of administrative claims linked with medical chart review.

Administrative claims provide a rich data source for retrospective studies of real-world clinical practice, yet some important data may be inconsistent or unavailable. This study explored factors influencing discontinuation of thrombopoietin receptor agonists (TPO-RAs) among patients with immune thrombocytopenia (ITP), by adding medical chart abstraction for additional details. Adult (≥ 18 years) patients with continuous commercial or Medicare Advantage with Part D health insurance coverage were included. Inclusion criteria were ≥ 1 claim for eltrombopag or romiplostim and ≥ 2 diagnoses of ITP between December 31, 2017, and January 1, 2020. Providers were asked to provide access to medical charts for abstraction. The analyses included only patients who discontinued TPO-RA and described patient characteristics, treatment patterns, platelet values, and reasons for discontinuation. Among 207 ITP patients treated with a TPO-RA, 137 (66%) discontinued treatment during the observation period. The mean TPO-RA treatment duration was 185 days. Mean platelet count at the time of discontinuation was 197 × 109/L. The most common reason for discontinuation was improvement of the patient's condition (42%). Other reasons included worsening of ITP/lack of response (12%), adverse events (12%), and cost-related or social reasons (23%). No reason was reported for 10%. Notably 26% of patients who discontinued remained off all ITP therapy for the remainder of the study, with a mean treatment-free period of 262 days. These results emphasize that some patients with ITP are able to discontinue TPO-RA therapy and achieve durable treatment-free periods.

Comparison of COPD health care utilization and associated costs across patients treated with LAMA+LABA fixed-dose therapies.

BACKGROUND: There is limited clinical trial and/or real-world evidence comparing differences among currently approved fixed-dose combination (FDC) long-acting muscarinic antagonist (LAMA)/long-acting beta2-agonist (LABA) treatments. OBJECTIVE: To compare chronic obstructive pulmonary disease (COPD)-related and all-cause health care resource utilization (HCRU) and costs between COPD patients initiating tiotropium (TIO) + olodaterol (OLO) versus (a) other LAMA + LABA FDCs and (b) umeclidinium (UMEC) + vilanterol (VI), specifically. METHODS: In this retrospective observational study, patients initiating fixed-dose LAMA + LABA therapy (earliest fill date = index date) between January 1, 2014, and September 30, 2018, were identified using administrative claims data from the Optum Research Database. Patients were followed post-index for 1-12 months. Follow-up was censored at the earliest occurrence of index therapy discontinuation or switch, health plan disenrollment, study end date, or reaching the maximum 12-month allowed duration. Propensity score matching of 1:2 was used to balance differences in baseline characteristics between cohorts for each of the 2 comparisons. Annualized population averages of HCRU and costs were calculated for each cohort as [sum of visits (or costs) for all individuals during the follow-up period] ÷ [sum of follow-up on-treatment time for all individuals] × 365 days. RESULTS: After matching, compared with patients who initiated other LAMA + LABAs or UMEC + VI, patients who initiated TIO + OLO had 14.29% and 16.95% fewer mean annualized per-patient COPD-related emergency department (ED) visits (vs. other LAMA + LABAs: 0.49 vs. 0.59, P = 0.005; vs. UMEC + VI: 0.48 vs. 0.56, P = 0.026) and 3.07% and 3.14% fewer mean annualized per-patient pharmacy fills (vs. other LAMA + LABAs: 12.66 vs. 13.07, P = 0.016; vs. UMEC + VI: 12.62 vs. 13.02, P = 0.022), leading to 17.39% and 21.47% lower mean annualized per-patient COPD-related ED costs (vs. other LAMA + LABAs: $289 vs. $368, P = 0.003; vs. UMEC + VI: $285 vs. $345, P = 0.027) and 4.56% and 5.67% lower mean annualized per-patient pharmacy spending (vs. other LAMA + LABAs: $3,570 vs. $3,741, P < 0.001; vs. UMEC + VI: $3,556 vs. $3,770, P < 0.001) in the follow-up period. Similarly, patients in the TIO + OLO cohort had 15.63% and 21.17% fewer mean annualized per-patient all-cause ED visits (vs. other LAMA + LABAs: 1.08 vs. 1.37, P < 0.001; vs. UMEC + VI: 1.08 vs. 1.28, P = 0.001), 8.29% fewer mean annualized per-patient outpatient visits (vs. UMEC + VI: 13.28 vs. 14.48, P = 0.031), 3.41% fewer mean annualized per-patient pharmacy fills (vs. other LAMA + LABAs: 56.92 vs. 58.93, P = 0.028), 19.48% and 22.28% lower mean annualized per-patient all-cause ED costs (vs. other LAMA + LABAs: $755 vs. $971, P < 0.001; vs. UMEC + VI: $749 vs. $930, P < 0.001), and 10.86% lower mean annualized per-patient outpatient setting costs (vs. UMEC + VI: $3,348 vs. $3,756, P = 0.050). There were no statistically significant differences for the other outcome measures. CONCLUSIONS: In a real-world setting, differences in HCRU and costs were observed between FDC LAMA + LABAs, with patients initiating TIO + OLO having lower ED visits/costs, COPD-related pharmacy fills/costs, and all-cause pharmacy use and outpatient visits/costs than those initiating other FDC LAMA + LABAs or UMEC + VI specifically. The remaining HCRU and cost measures were not significantly different. DISCLOSURES: This study was sponsored by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI; Ridgefield, CT). BIPI was given the opportunity to review the manuscript for medical and scientific accuracy, as well as intellectual property considerations. Palli is an employee of BIPI. Xie, Chastek, Elliott, and Bengtson are employees of Optum, which was contracted by BIPI to conduct this study. The authors received no direct compensation related to the development of the manuscript. Part of the results of this study were accepted and presented at the 30th European Respiratory Society (ERS) International Congress (September 7-9, 2020; virtual).

Healthcare Resource Utilization, Exacerbations, and Readmissions Among Medicare Patients with Chronic Obstructive Pulmonary Disease After Long-Acting Muscarinic Antagonist Therapy Initiation with Soft Mist versus Dry Powder Inhalers.

Background: Chronic obstructive pulmonary disease (COPD) is often managed with inhaled long-acting muscarinic antagonists (LAMAs), yet real-world data on healthcare resource utilization (HRU) by inhaler type are lacking. This study compared HRU after LAMA initiation with a soft mist inhaler (SMI) versus a dry powder inhaler (DPI). Patients and Methods: Inclusion criteria were COPD diagnosis, age ≥40 years, LAMA initiation (index date = first LAMA SMI or DPI claim 9/1/14-6/30/18), and Medicare Advantage enrollment 1 year pre-index (baseline) to ≥30 days post-index (follow-up). Patients were followed to the earliest of discontinuation, switch, disenrollment, 1 year, or study end (7/31/18). Exclusion criteria were asthma, cystic fibrosis, or lung cancer diagnoses, unavailable demographics, multiple index LAMAs, or baseline LAMA use. Cohorts (SMI or DPI) were balanced on baseline characteristics using inverse probability of treatment weighting. Outcomes included per patient per month (PPPM) COPD-related HRU encounters, and exacerbations (defined as moderate [ambulatory visit with corticosteroid or antibiotic within ±7 days] or severe [emergency visit or inpatient admission]); and 30-day readmissions following COPD-related hospitalizations. Results: After weighting, cohorts (SMI [n=5360] and DPI [n=22,880]) were similar in age (72 and 73 years, respectively), gender (both 52% female), and COPD severity score (31.3 and 31.5, respectively). Cohorts had similar counts of follow-up HRU encounters. However, the SMI cohort had fewer (mean ± standard deviation) COPD-related exacerbations (0.054±0.082 vs DPI cohort 0.059±0.088 PPPM, p<0.001) overall. Moreover, the SMI cohort had fewer severe exacerbations (0.030±0.058 vs DPI: 0.034±0.065 PPPM, p<0.001). Hospitalizations among SMI patients had a lower adjusted odds of readmission versus hospitalizations among DPI patients (odds ratio: 0.656, 95% confidence interval= 0.460, 0.937; p=0.020). Conclusion: SMI initiators had significantly fewer COPD-related exacerbations than DPI initiators. In addition, lower odds of readmissions were observed following COPD-related hospitalizations among the SMI cohort, as compared with the DPI cohort.

Symptom Burden and GOLD Classification in Medicare Advantage Patients with COPD Initiating Umeclidinium/Vilanterol or Fluticasone Propionate/Salmeterol Therapy.

Background: Long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) provide greater improvements in lung function and symptoms than inhaled corticosteroid (ICS)/LABA in patients with chronic obstructive pulmonary disease (COPD). This study evaluated symptom burden and Global Initiative for Obstructive Lung Disease (GOLD) categorization among patients who recently initiated umeclidinium/vilanterol (UMEC/VI; LAMA/LABA) or fluticasone propionate/salmeterol (FP/SAL; ICS/LABA) single-inhaler dual therapy. Methods: COPD-diagnosed Medicare Advantage enrollees aged ≥65 years were identified from the Optum Research Database (ORD). Eligible patients had ≥1 pharmacy claim for UMEC/VI or FP/SAL in the 6-month period before sample identification, with no evidence of triple therapy (ICS/LAMA/LABA), asthma, or lung cancer. Symptom burden was assessed via cross-sectional surveys using the COPD Assessment Test (CAT) and modified Medical Research Council (mMRC) dyspnea scale. Patients were classified into GOLD categories using patient-reported symptoms and claims-based exacerbation history. Treatment groups were balanced on potential confounders using inverse probability of treatment weighting (IPTW). CAT and mMRC scores were analyzed with generalized linear regression models using IPTW propensity scores. Results: The final analytic sample included 789 respondents (UMEC/VI: N=392; FP/SAL: N=397). Approximately 66% patients were classified as GOLD B when assessing symptoms with CAT and mMRC together, or CAT alone; more patients were classified as GOLD A (~40%) than GOLD B (~36%) using mMRC alone. Proportions of patients in each GOLD group were similar between treatment cohorts. Post-IPTW multivariable modeling showed similar symptom burden between treatment groups. Conclusion: After controlling for baseline characteristics, symptom burden was similar between patients receiving UMEC/VI or FP/SAL. GOLD classification using mMRC produced more conservative results compared with CAT, potentially underestimating patient symptoms. Many patients receiving FP/SAL were classified as GOLD A or B, despite GOLD recommending non-ICS-containing therapy in these patients. These findings support the need for routine assessment of symptoms in patients with COPD.

Retrospective Database Analysis of Treatment Patterns Among Patients with Pulmonary Arterial Hypertension.

INTRODUCTION: Release of the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines put increased emphasis on using combination therapy, either as upfront or sequential therapy among patients with pulmonary arterial hypertension (PAH). However, with these recommendations and the therapy advances made in the last several years, little is known on the real-world treatment patterns among patients with PAH, particularly before and after publication of the 2015 ESC/ERS guidelines. METHODS: This was a retrospective study of adult commercial and Medicare Advantage with Part D (MAPD) enrollees with at least one claim for a PAH-related medication from January 01, 2012 to March 31, 2017, at least one medical claim with a pulmonary hypertension diagnosis, and continuous health plan enrollment at least 6 months prior to and at least 12 months following the date of the first pharmacy claim for PAH-related therapy (index date). Patients were divided into cohorts based on prescription of monotherapy or combination therapy and index date category (2012-2013, January 2014-July 2015, and August 2015-March 2017). RESULTS: Out of 1878 patients, 90.8% initiated with monotherapy and 9.2% initiated with combination therapy. The percentage of patients with index combination therapy increased from 5.7% in 2012-2013 to 13.0% in August 2015-March 2017. Patients with index combination therapy had better persistence (11.6 months versus 10.3 months) and adherence (0.95 versus 0.85). Overall, the discontinuation rate was 40% and was higher in monotherapy versus combination therapy patients (42.8% versus 12.2%). Approximately 30.2% of patients had a second regimen, of which 50% were combination regimens. The time to combination therapy initiation decreased from 10.5 months in 2012-2013 to 3.4 months in August 2015-March 2017. CONCLUSIONS: The majority of patients initiated monotherapy treatment for PAH, most often a phosphodiesterase 5 inhibitor (PDE5i). Patients with upfront combination therapy increased following publication of the 2015 ESC/ERS guidelines, indicating that physicians responded to the guideline's option of prescribing upfront combination therapy.

Baseline history of patients using selexipag for pulmonary arterial hypertension.

INTRODUCTION: Since its introduction to the market in 2016, selexipag has been an alternative oral therapy among both treatment-naïve patients and those with mono or dual therapy failure; however, limited information is available regarding the presentation and management of patients with pulmonary arterial hypertension (PAH) prior to selexipag initiation. This study examined treatment patterns, healthcare utilization, and costs in the 12 months prior to and the 6 months following selexipag initiation. METHODS: This was a retrospective study of adult commercial and Medicare Advantage with Part D (MAPD) health plan members with a medical or pharmacy claim for selexipag from 1 January 2016 through 31 May 2017, a diagnosis of pulmonary hypertension, and continuous health plan enrollment for 12 months prior to selexipag initiation (baseline period). Treatment patterns, healthcare utilization, and costs were measured over the baseline period and the 6 months following selexipag initiation (among patients with ⩾6 months of follow up). RESULTS: After inclusion and exclusion criteria were applied, 95 patients were included in the analysis. At study start, 57.9% of patients were prescribed combination therapy, increasing to 69.5% immediately prior to selexipag initiation. Approximately 60% of patients had one baseline regimen. Emergency visits and inpatient admissions during the baseline period occurred in 63.2% and 48.4% of patients, respectively. Baseline medical costs rose steadily, increasing 266.8% in commercial and 26.7% in MAPD enrollees from the beginning to the end of the 12-month baseline period. PAH-related healthcare costs accounted for more than 80% of total costs. Mean medical costs in the 6 months following selexipag initiation were US$17,215 in commercial and US$23,976 in MAPD enrollees. CONCLUSIONS: The majority of patients with PAH remained on the same therapy in the 12 months prior to selexipag initiation despite high rates of healthcare utilization and increasing costs. Mean medical costs appeared to decrease after adding or switching to selexipag.

Incidence of febrile neutropenia during chemotherapy among patients with nonmyeloid cancer receiving filgrastim vs a filgrastim biosimilar.

BACKGROUND: Filgrastim and other granulocyte colony-stimulating factors are recommended to decrease febrile neutropenia (FN) incidence among patients with nonmyeloid cancers undergoing chemotherapy. Data comparing biosimilar filgrastim-sndz with reference filgrastim (filgrastim-ref) are limited outside of clinical trials in the US. OBJECTIVE: To compare the incidence of FN across chemotherapy cycles 1-6 between patients treated with filgrastim-sndz vs filgrastim-ref. MATERIALS AND METHODS: This was a retrospective claims analysis of patients with nonmyeloid cancer enrolled in commercial or Medicare Advantage plans from March 2015 to June 2016 and receiving filgrastim-sndz or filgrastim-ref during ≥1 completed chemotherapy cycle. Patients undergoing hematopoietic stem cell transplantation, pregnant patients, and those with missing data were excluded. FN was identified using the diagnosis codes for neutropenia + fever, neutropenia + bacterial/fungal infection, and neutropenia + infection + fever. Equivalence testing for FN incidence at the cycle level across chemotherapy cycles 1-6 was conducted for filgrastim-sndz vs filgrastim-ref after adjusting for baseline characteristics using inverse probability of treatment weighting. Results were considered equivalent if the 90% CIs for between-cohort differences were within ±6.0%. RESULTS: The analysis included 3,459 patients (162 filgrastim-sndz and 3,297 filgrastim-ref). Before weighting, the filgrastim-sndz cohort was younger than filgrastim-ref and had a higher proportion of men, a higher proportion with commercial insurance, and lower proportions with granulocyte colony-stimulating factor prophylaxis or metastatic cancer. After weighting, baseline characteristics were similar between cohorts. Adjusted FN incidence was equivalent for filgrastim-sndz vs filgrastim-ref, respectively: neutropenia + fever, 0.81% vs 0.61% (difference [90% CI]=0.20 [-0.57 to 1.56]); neutropenia + infection, 1.21% vs 1.33% (difference [90% CI]=-0.12 [-1.17 to 2.28]); neutropenia + infection + fever, 0.0% vs 0.14% (difference=-0.14; CI not calculated because filgrastim-sndz had 0 events). CONCLUSION: Filgrastim-sndz and filgrastim-ref are statistically equivalent for preventing FN across chemotherapy cycles 1-6 among patients with nonmyeloid cancer.

Clinical Outcomes of Treatment with Filgrastim Versus a Filgrastim Biosimilar and Febrile Neutropenia-Associated Costs Among Patients with Nonmyeloid Cancer Undergoing Chemotherapy.

BACKGROUND: Granulocyte colony-stimulating factors such as filgrastim are used to decrease the incidence of febrile neutropenia (FN) among patients with nonmyeloid cancers undergoing chemotherapy treatment. Although the biosimilar filgrastim-sndz has been approved in the United States since 2015, limited real-world comparisons of filgrastim-sndz versus reference filgrastim (filgrastim-ref) have been conducted. OBJECTIVE: To compare FN incidence and assess overall FN-related health care resource utilization and medical costs among U.S. patients with non-myeloid cancer who received filgrastim-sndz or filgrastim-ref during their first chemotherapy cycle. METHODS: This was a retrospective claims analysis of patients with non-myeloid cancer who were enrolled in commercial or Medicare Advantage insurance plans from March 2015 through June 2016 and received filgrastim-sndz or filgrastim-ref during their first observed chemotherapy cycle. Patients with evidence of hematopoietic stem cell transplantation or pregnancy and those with missing demographic information were excluded. FN was defined on the basis of diagnosis codes for neutropenia and fever (N/F); neutropenia and infection (N/I); and neutropenia, infection, and fever (N/I/F). Cohorts were adjusted for differences in baseline patient characteristics using the inverse probability of treatment weighting (IPTW) method, and equivalence testing was used to compare the proportion of patients who developed FN between weighted cohorts. On the basis of the range of neutropenic fever incidence found in the PIONEER clinical trial, FN incidence was considered equivalent if 90% CIs for between-cohort differences were within ± 6%. Mean FN-related health care resource utilization and total FN-related medical costs were calculated for the overall study population. RESULTS: A total of 3,542 patients were included in the study (172 filgrastim-sndz; 3,370 filgrastim-ref; mean ages 62.1 years and 64.7 years, respectively). After IPTW, there were 162 patients in the filgrastim-sndz cohort and 3,297 in the filgrastim-ref cohort (mean age 64.5 years for both). FN incidence in the weighted filgrastim-sndz versus filgrastim-ref cohorts, respectively, was 1.4% versus 0.9% for N/F, 2.3% versus 1.7% for N/I, and 0.0% versus 0.3% for N/I/F; FN incidence was statistically equivalent between treatment cohorts. Among patients in either treatment cohort who developed FN, the proportion with FN-related inpatient stays during the first chemotherapy cycle ranged from 35.0% for N/I to 70.0% for N/I/F. Mean (SD) FN-related total medical costs across all patients who developed FN were $11,977 ($18,383) for N/F, $8,040 ($14,809) for N/I, and $21,733 ($30,003) for N/I/F, in 2015 U.S. dollars. For all 3 definitions of FN, the largest proportions (73.5%-93.4%) of medical costs were inpatient related. CONCLUSIONS: In this real-world study of patients with nonmyeloid cancers undergoing chemotherapy, the incidence of FN was statistically equivalent between individuals treated with filgrastim-sndz versus filgrastim-ref during their first chemotherapy cycle. FN-related health care resource utilization and medical costs among patients who developed FN were substantial. DISCLOSURES: This work was funded by Sandoz, which participated in the study design, data interpretation, writing and revision of the manuscript, and decision to submit the manuscript for publication. Balu and Campbell are employees of Sandoz, which is the manufacturer of the filgrastim biosimilars Zarzio and Zarxio. DeLeon was an employee of Sandoz at the time this study was conducted. Lal, Brekke, Elliott, and Korrer are employees of Optum, which was contracted by Sandoz to conduct this study.

Inhaled Corticosteroid-Containing Treatment Escalation and Outcomes for Patients with Asthma in a U.S. Health Care Organization.

BACKGROUND: Asthma is a common disorder that affects approximately 8% of the U.S. POPULATION: Treatment guidelines indicate inhaled corticosteroids (ICS) as the mainstay treatment, yet poor asthma control is common among ICS-treated patients. Treatment escalation (ICS dose increase and other controller therapy add-ons) is used to manage symptoms. Real-world studies of postescalation outcomes may inform treatment decisions. OBJECTIVES: To (a) describe characteristics and treatment patterns among asthma patients who escalated treatment and (b) assess outcomes (exacerbations, uncontrolled asthma, and health care resource utilization [HCRU]) after escalation. METHODS: The study cohort was identified from a large U.S. administrative claims database via ICD-9-CM codes for asthma (493.xx on ≥ 2 dates) and initiation (defining index date) of long-term (> 1 fill) ICS-containing treatment between January 1, 2009, and September 30, 2014. One year of continuous enrollment was required before and after the index date. Escalation was defined as ≥ 1 of the following: ICS dose increase; a switch between ICS, long-acting beta-2 agonists (LABA), or leukotriene modifiers (LTRM) to a different ICS, LABA, or LTRM; or add-on of controller medications (e.g., antibody biologic). Escalation patterns were examined. Rates of exacerbation (defined by inpatient admission, emergency department [ED] visit, or office visit with a pharmacy claim for an oral corticosteroid [OCS] within 7 days) and occurrence of uncontrolled asthma (defined by > 4 fills for a short-acting beta agonist [SABA] in a 1-year period, ≥ 1 OCS fill, or ≥ 1 asthma-related ED visit or inpatient admission) were calculated. Per-patient-per-year (PPPY) HCRU was estimated. RESULTS: Among 35,126 patients (mean [SD] age 38 [16] years) who initiated long-term ICS-containing treatment, 5,044 (14%) patients escalated their index regimens at 136 (105) days post-index (i.e., pre-escalation period). The most frequent changes, alone or in combination, included ICS dose increase (68%) or LABA (27%) or LTRM (25%) add-ons. Before escalation, the exacerbation rate was 1.60 (5.10) PPPY, and 1,108 (22%) patients experienced exacerbation. During the postescalation period of 251.6 (138.9) days, the exacerbation rate was 0.75 (2.9) PPPY, and 1,038 (21%) patients experienced exacerbation. A majority (> 85%) of exacerbations in the periods before and after escalation were associated with an office visit plus an OCS pharmacy claim within 7 days. Uncontrolled asthma was experienced by 41.5% and 41.0% of patients before and after escalation, respectively. Ambulatory care visits were common before (mean [SD] 24.0 [26.7] all-cause and 8.5 [13.4] asthma-related PPPY) and after escalation (19.3 [21.3] all-cause and 4.6 [8.1] asthma-related PPPY). CONCLUSIONS: Among asthma patients who initiated a long-term ICS-containing regimen, approximately 14% escalated therapy within a year of initiation. Yet, 21% of those patients had ≥ 1 exacerbation, and 41% of patients had uncontrolled asthma within 1 year after treatment escalation. The results demonstrate an unmet need among asthma patients who escalated their ICS-containing treatment. DISCLOSURES: This study was sponsored and funded by Boehringer-Ingelheim, which contracted with Optum to conduct the research. The sponsor collaborated with Optum on the preparation, writing, revision, and approval of the manuscript. Bengston, Cao, Hulbert, Wolbeck, Elliott, and Buikema are employees of Optum. Yu and Wang are employed by Boehringer-Ingelheim. Study concept and design were contributed by Bengston, Yu, and Wang. Cao, Hulbert, and Wolbeck collected the data, and data analysis was performed by Bengston, Yu, and Wang. The manuscript was written by Bengston, along with Yu and Wang, and revised by Bengston, Yu, and Wang, along with the other authors.